title: Integrated molecular analysis of clear-cell renal cell carcinoma.
abstract: Clear-cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and its molecular pathogenesis is incompletely understood. Here we report an integrated molecular study of ccRCC in which ≥100 ccRCC cases were fully analyzed by whole-genome and/or whole-exome and RNA sequencing as well as by array-based gene expression, copy number and/or methylation analyses. We identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures and determined their impact on tumor behavior. Defective VHL-mediated proteolysis was a common feature of ccRCC, which was caused not only by VHL inactivation but also by new hotspot TCEB1 mutations, which abolished Elongin C-VHL binding, leading to HIF accumulation. Other newly identified pathways and components recurrently mutated in ccRCC included PI3K-AKT-mTOR signaling, the KEAP1-NRF2-CUL3 apparatus, DNA methylation, p53-related pathways and mRNA processing. This integrated molecular analysis unmasked new correlations between DNA methylation, gene mutation and/or gene expression and copy number profiles, enabling the stratification of clinical risks for patients with ccRCC.
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.forename: Tetsuichi
authors.initials: T
authors.lastname: Yoshizato
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Shigekatsu
authors.initials: S
authors.lastname: Maekawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Takumi
authors.initials: T
authors.lastname: Kamura
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Ayana
authors.initials: A
authors.lastname: Kon
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujimoto
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.forename: Haruki
authors.initials: H
authors.lastname: Kume
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002460:Cell Line; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D000075065:Elongin; D059472:Exome; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D009154:Mutation; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C000616395:ELOC protein, human; D000075065:Elongin; D051793:Hypoxia-Inducible Factor 1; D014157:Transcription Factors